Original Article Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: Focusing on mitochondrial DNA depletion syndrome Taro Yamazaki, 1,6 Kei Murayama, 3 Alison G Compton, 6 Canny Sugiana, 6 * Hiroko Harashima, 1 Shin Amemiya, 1 Masami Ajima, 3 Tomoko Tsuruoka, 3 Ayako Fujinami, 3 Emi Kawachi, 3 Yoshiko Kurashige, 4 Kenshi Matsushita, 4 Hiroshi Wakiguchi, 4 Masato Mori, 5 Hiroyasu Iwasa, 2 Yasushi Okazaki, 2 David R Thorburn 6 and Akira Ohtake 1 1 Department of Pediatrics, Faculty of Medicine and 2 Translational Research Center, International Medical Center, Saitama Medical University, Saitama, 3 Department of Metabolism, Chiba Children’s Hospital, Chiba, 4 Department of Pediatrics, Kochi Medical School Kochi University, Kochi, 5 Department of Pediatrics, Jichi Medical University, Tochigi, Japan and 6 Murdoch Childrens Research Institute, Royal Children’s Hospital and Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Abstract Background: Although mitochondrial respiratory chain disorders (MRCD) are one of the most common congenital metabolic diseases, there is no cumulative data on enzymatic diagnosis and clinical manifestation for MRCD in Japan and Asia. Methods: We evaluated 675 Japanese patients having profound lactic acidemia, or patients having symptoms or signs of multiple-organ origin simultaneously without lactic acidemia on respiratory chain enzyme activity assay and blue native polyacrylamide gel electrophoresis. Quantitative polymerase chain reaction was used to diagnose mitochondrial DNA depletion syndrome (MTDPS). Mutation analysis of several genes responsible for MTDPS was also performed. Results: A total of 232 patients were diagnosed with a probable or definite MRCD. MRCD are common, afflicting one in every several thousand people in Japan. More than one in 10 of the patients diagnosed lacked lactic acidemia. A subsequent analysis of the causative genes of MTDPS identified novel mutations in six of the patients. A 335 bp deletion in deoxyguanosine kinase (DGUOK; g.11692_12026del335 (p.A48fsX90)) was noted in two unrelated families, and may therefore be a common mutation in Japanese people. The proportion of all patients with MTDPS, and particularly those with recessive DNA polymerase γ (POLG) mutations, appears to be lower in Japan than in other studies. This is most likely due to the relatively high prevalence of ancient European POLG mutations in Caucasian populations. No other significant differences were identified in a comparison of the enzymatic diagnoses, disease classifications or prognoses in Japanese and Caucasian patients with MRCD. Conclusion: MTDPS and other MRCD are common, but serious, diseases that occur across all races. Key words DGUOK deletion mutation, enzymatic diagnosis, mitochondrial DNA depletion syndrome, mitochondrial respiratory chain disorder, racial difference. Mitochondrial respiratory chain disorders (MRCD) are disorders of the oxidative phosphorylation system, which is responsible for ATP production. MRCD are the most common congenital metabolic diseases, afflicting at least 1 in 5000 persons. 1 Mitochondrial DNA depletion syndrome (MTDPS), in which mitochondrial DNA (mtDNA) level is lower than normal, is one of the major MRCD. A number of responsible genes of MTDPS have been identified, and the pathophysiology of this disease is partially characterized at the molecular level. 2–5 We have previ- ously diagnosed and characterized MRCD cases in Japan using respiratory chain enzyme analysis. 6–9 Having recently analyzed the molecular diagnoses and clinical manifestations of MRCD in Japanese patients, and analyzing several genes responsible for hepatocerebral MTDPS, we herein discuss and compare the col- lected data to those reported for MRCD outside of Japan. Methods Patients and samples The subjects consisted of patients clinically suspected of having MRCD. We measured respiratory chain enzyme activity and quantity for patients with profound lactic acidemia, or patients with symptoms or signs of multiple-organ origin simultane- ously without lactic acidemia. Other metabolic disorders were excluded on plasma tandem mass spectrometry and urine organic acid analysis. Approximately half of candidates were <1 year old, Correspondence: Akira Ohtake, MD PhD, Department of Pediatrics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan. Email: akira_oh@ saitama-med.ac.jp *Present address: Monash IVF PTY Ltd, Melbourne, Victoria, Australia. Received 11 July 2013; revised 19 August 2013; accepted 21 October 2013. Pediatrics International (2014) 56, 180–187 doi: 10.1111/ped.12249 © 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society